Acute renal failure (ARF) occurs in approximately 1% to 25% of critically ill patients depending upon the population being studied and the criteria used to define its presence. For example, ARF complicating a nonrenal organ failure in the intensive care unit (ICU) is associated with a mortality of around 50% to 70%. This statistic has not improved significantly over the last five decades (1–7). In addition, it is well established that the development of ARF is independently associated with an increase in mortality (2, 8–11).
In the past, several agents have been used as potential treatments of ARF to impact the high mortality associated with ARF; however, none of them have been successful. One principle reason for the failure of these therapeutic interventions in clinical trials of ARF is the dependency of serum creatinine as a screening process for initial enrollment of patients, for the diagnosis of ARF and for initiating the intervention. ARF has been typically diagnosed by a progressive rise in serum creatinine over several days, which may or may not be associated with oliguria, (decreased urine output for example producing less than 500 ml of urine in 24 hours).
Because of the vital importance of earlier administration on the success rate of therapies, many markers have been explored for early diagnosis of ARF. Several cytokines and molecules have been analyzed as potential early markers of ARF. Although the initial studies on some molecules like tubular enzymes, growth factors, adhesion molecules and some cytokines (14–16, 29–31) were promising, subsequent studies have shown inadequate sensitivity or specificity to advocate clinical use for diagnosis. Recently described molecules such as kidney injury molecule-1 (KIM-1), cystein-rich protein 61 (Cry61), neutrophil gelatinase-associated lipocalin (NGAL) and sodium/hydrogen exchanger isoform 3 (NHE3) have demonstrated results as markers of ARF at the pre-clinical level (14–16, 29–31). However, to date, none of these molecules have been systematically explored in human ARF diagnosis.
Renal hypoperfusion or ischemia account for about 50% of the cases of ARF (1, 2). The main functional problem in these patients is a decrease in GFR (glomerular filtration rate) and its consequent effects on uremic toxin accumulation, fluid, electrolyte and acid-base balance. The course of the illness is highly variable ranging from a transient disease lasting less than one week and associated with full recovery of renal function, to a disease persisting for longer than one month and requiring dialysis and intensive care management. There is no clear relationship between the severity of the initial ischemic insult and the course of the illness. However, there is a correlation between the duration of the kidney dysfunction and mortality from ARF. Fresh renal ischemic lesions have been found in biopsy or autopsy specimens of patients with ARF as late as 3 weeks after the initial ischemic event (4). Thus, a better understanding of the pathogenesis of ARF is needed to allow interventions which would prevent the need for hemodialysis, shorten the course of ARF and improve survival. The virtual complete recovery of renal function in those patients who survive ARF, as well as the minimal renal histological abnormalities during ARF when the GFR is less than 10 ml/min, suggest that there are reversible components in the pathophysiology of ARF. In addition, ARF is a common life threatening complication following allogeneic hematopoietic stem cell transplant (HSCT), previously termed a bone marrow transplant, Thus, early detection of ARF is imperitive for early intervention and treatment.
Because early intervention of renal disfunction is critical, a need exists for the detection of early signs that predict the onset of the condition. The present invention, concerns the detection of an indicator molecule to predict the onset of organ failure. The detection of this indicator can alert a medical practitioner that treatment may be required immediately to attenuate the condition and possibly prevent full onset of organ shutdown and death.